All fatty liver diseases, including fatty liver that is similar to alcoholic liver disorder which occurs to non-drinkers, are referred to as non-alcoholic fatty liver disease (NAFLD). In NAFLD patients, fatty acid synthesis in the liver is always activated, and the activation of fatty acid synthesis is an important factor involved in fatty liver development which is caused by metabolic syndrome.
NAFLD is roughly categorized into two groups: simple fatty liver which is generally thought of as having a mild prognosis, and non-alcoholic steatohepatitis (NASH), which is thought of as having a poor prognosis since simple fatty liver is continuously accompanied by inflammation or fibrosis, and NASH is regarded as one of the severe types of NAFLD.
Up to now, the Two-Hit theory has been known as the main pathologic mechanism of the occurrence and development of NASH. The Two-Hit theory is that the First Hit, which means factors such as life habits or genetic factors, develops simple fatty liver, and then multiple factors such as oxidative stress or inflammatory cytokines mainly induced at the fatty liver state act as the Second Hit to aggravate simple fatty liver to the severe stage of NASH.
The treatment for metabolic syndrome—which is known as one of the factors associated with occurrence of NASH—is very important, and in view of this aspect, medicaments—which have inhibitory effect against the metabolic syndrome such as insulin resistance improving agent, antioxidant, hyperlipidemia treatment agent, liver protecting agent, and antagonist of angiotensin II receptor—were tried clinically.
However, little development has been made on medicaments with clinical evidence for the treatment of NASH until now. For example, pioglitazone—which is an insulin resistance improving agent—was very promising as a medicament for the treatment of NASH, but it did not show practical improving effects in the phase 3 clinical trial, and it failed to obviously meet the standards for treatment medication due to problems of side effects such as risk of fracture, weight gain, heart failure deterioration and crisis.
Therefore, there has been an urgent need for studies about the prevention or treatment of non-alcoholic steatohepatitis.
Meanwhile, (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1H-indol-7-yl]amine is a cellular necrosis inhibitor which is specific for mitochondria, and shows effects on inhibiting cell death by toxins or stress, increasing viability of cells, and anti-oxidation and anti-inflammation at the same time.
In other words, although (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1H-indol-7-yl]amine is known to be effective for various diseases related to cellular necrosis, there has been no disclosure related to the prevention and treatment of fatty liver disease and metabolic syndrome, and no study has been conducted on this issue.
The present inventors accomplished the present invention by discovering that the treatment of the NASH animal model with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1H-indol-7-yl]amine effectively improves fatty liver, liver inflammation and liver fibrosis—which are the main pathological forms of NASH.